Benzimidazoles were originally developed as plant fungicides and later as veterinary and human anthelmintics. The family of benzimidazoles with anthelmintic activity includes thiazolyl benzimidazoles and benzimidazole carbamates. The benzimidazoles show a broad spectrum of activity against helminth parasites. Well known benzimidazoles with activity against helminths are for example thiabendazole; cambendazole; and benzimidazole carbamates, such as parbendazole (U.S. Pat. No. 3,480,642), mebendazole (U.S. Pat. No. 3,657,267), flubendazole (U.S. Pat. No. 3,657,267), fenbendazole (U.S. Pat. No. 3,954,791), oxfendazole (U.S. Pat. No. 3,929,821), oxibendazole (U.S. Pat. No. 3,574,845), albendazole (U.S. Pat. No. 3,915,986), ricobendazole (albendazole sulfoxide) (U.S. Pat. No. 3,915,986) and luxabendazole (U.S. Pat. No. 4,639,463), all of which differ in the substituents on the parent benzimidazole nucleus.
Benzimidazoles are believed to owe their activity to the fact that they block the polymerization of beta-tubulin into microtubules. This affects the transport functions of cells within the parasite and ultimately kills the parasite.
Phenylguanidine prodrugs that are metabolically transformed into anthelmintic benzimidazoles have also been developed. Febantel (U.S. Pat. No. 3,993,682), for example, is a prodrug that is converted into fenbendazole, and netobimin (U.S. Pat. No. 4,406,893) yields albendazole.
Benzimidazoles are generally poorly soluble in water. They are given per oral as a suspension, paste or powder, or by intraruminal injection (McKellar and Scott, J. Vet. Pharmacol. Therap., 13, 223-247, 1990). The fact that benzimidazoles, and especially benzimidazole carbamates, are poorly soluble in water limits their applications. In particular, the solubility of the benzimidazole carbamates is extremely low, probably due to the presence of the carbamate group on the benzimidazole moiety. These compounds are practically insoluble in water. For some useful applications of the compounds, such as the use in aquaculture applications and drinking water applications, the poor water solubility of the benzimidazoles is a major obstacle.
A lot of effort has already been put into solving the problem of poor- or non-aqueous solubility of benzimidazole(carbamate)s.
Attempts have also been made to provide more soluble derivatives of benzimidazoles (prodrugs, which are metabolized into the active compound). The efficacy of a prodrug depends on many factors, such as the rate and the extent to which the prodrug is converted into the active substance and the site of this transformation. Moreover the prodrug should possess high solubility in water at the pH of maximal stability, and sufficient aqueous stability prior to the application. Of course the prodrug should be well tolerated and should not be more toxic than the active compound.
Efforts regarding benzimidazole prodrugs were undertaken in the context of the use of the benzimidazoles in the combat of systemic infections, for example with the larval stage of the cestodes, Echinococcus multicularis and E. granulosis. In these cases plasma and tissue levels of the drugs are important since, in order to act systemically, the benzimidazoles have to be taken up into the bloodstream.
Certain albendazole prodrugs are described by Hernández-Luis et al. in Bioorganic & Medicinal Chemistry Letters, 11, 1359-1362, 2001. Hernández-Luis et al. attempted to enhance the solubility of albendazole by synthesizing three N-acyl and two N-alkoxycarbonyl derivatives. These derivatives were developed mainly in the context of the use of albendazole prodrugs for some tissue dwelling infestations such as trichinellosis, hydrated disease (echinococcsis) and neurocysticerosis, where high doses and long treatment are required due to the poor solubility and absorption of albendazole.
Another group, Nielsen et al. (Acta Pharm. Nord., 4(1), 43-49, 1992) made prodrugs of thiabendazole by N-acylation of the benzimidazole moiety with various chloroformates as well as by acylmethylation, also with the aim of improving solubility of the benzimidazoles for use against hydrated disease. One N-(4-amino-methylbenzoyl)oxymethyl derivative was reported to have a 300-fold increased water solubility. However, this type of compound is not particularly stable towards hydrolysis, and would therefore be unsuitable, for example, for drinking water applications. Its solubility is also still insufficient to be used in drinking water applications. Moreover, it should be noted that 4-aminomethylbenzoic acid has been used as an antibrinolytic agent (Kloecking, H. P.; Markwardt, F., Haematologia, Supplement 1, 175-9, 1970), suggesting that the cleaved pro-moiety is not pharmacologically inactive. The Nielsen group also reported N-alkoxycarbonyl derivatives of mebendazole in Int. J. Pharm., 104,175-179, 1994.
Mannich bases of albendazole and fenbendazole were prepared by Dhaneshwar et al., Indian drugs, 28(1), 24-26, 1990, using various secondary amines such as dimethylamine, dipropylamine, pyrrolidine, piperazine, etc. Further Mannich bases are described in Garst et al. (U.S. Pat. No. 6,093,734). However, actual activity has not been demonstrated for the Mannich bases, and these derivative show very low stability in water.
A water soluble prodrug of albendazole exists, namely netobimin. But although netobimin is water soluble, it has been reported to cause embryonal toxicity.
In WO9312124 another class of benzimidazoles is discussed, namely substituted 2-[[(3,4-dialkoxy-2-pyridinyl)-methyl]sulfonyl]-1(H)-benzimidazole-1-yl compounds. These benzimidazoles are gastric acid secretion inhibitors (proton pump inhibitors) and structurally resemble well-known gastric acid secretion inhibitors like omeprazole and lansoprazole. In contrast to the benzimidazole carbamates, which are practically insoluble in water, the benzimidazole proton pump inhibitors are markedly more soluble in water. For example, omeprazole has a solubility of 500 μg/mL
In WO9312124 derivatives of these proton pump inhibitors are listed that are modified to contain a phosphonooxymethyl group attached as an N-substituent in position 1 on the benzimidazole nucleus. The thus modified compounds have the beneficial effect that they do not block the uptake of iodine into the thyroid gland. Furthermore the compounds are said to have a high solubility and chemical stability in water. It is believed that these compounds are metabolized at the N-substituent in position 1 of the benzimidazole nucleus before exerting their effect, which in effect makes them prodrugs. A syrup for oral administration of the compounds containing 1 g/L was prepared, as well as a solution for intravenous administration containing 4 mg/mL and 6 mg/mL.
Anthelmintic benzimidazole carbamates such as fenbendazole have much lower solubilities, being even lower than 0.05 μg/mL (Nguomo, A. J. PhD. Thesis, 1983, cited by McKellar et al. in J. Vet. Pharmacol. Therap. 1990, 13, 223-247).
Since benzimidazole carbamates are administered to, for example, poultry and pigs at large production farms, it would be convenient if the compounds could be administered via medicated drinking water. However, due to their very low solubility, administration via drinking water is highly problematic.
For drinking water applications, a lot of effort has been put into finding a suitable formulation for the compounds that assures accurate dosing. The problem with suspensions and emulsions of water insoluble drugs is that, in order to assure accurate dosing via a drinking water system, the suspension or emulsion must be uniform and very stable. EP1214052, for example, is concerned with a suspoemulsion for flubendazole, which is intended for use in drinking water applications.
Rather than preparing a suspension or emulsion, it would be more convenient if water soluble alternatives could be provided, for example, modified derivatives of the original, non-soluble active compounds, that still have the desired activity, or are converted in vivo to the actual active substances. But especially drinking water applications demand a very high solubility. For a drinking water application of any drug, usually a concentrate needs to be produced first, which requires even higher solubility of the drug. The compound should also dissolve in a short period of time. Moreover, if any compound which is to be administered via drinking water does not dissolve properly, or settles after a while, it may deposit in the pipes of a drinking water system, and the whole system may get clogged.
Because the drinking water may stand in the tanks or pipes of a drinking water system for a prolonged period of time, the compounds that are dissolved also need to be chemically very stable. If the compounds are not chemically stable over a prolonged period of time, none, or an insufficient quantity, of the actual active compound may reach the animals drinking the water. Especially for drinking water applications, a stability of at least 8 hours at a pH range from 5 to 9 is required.
A guideline on “quality aspects of pharmaceutical veterinary medicines for administration via drinking water” (EMEA/CVMP/540/03) was published by the European Medicines Agency (EMEA). In this guideline quality data requirements are reflected for veterinary medicinal products that are administered in drinking water to animals. The guideline provides, for example, criteria for the stability and solubility of the products and the time taken for them to fully dissolve.
Thus, especially for drugs that are to be administered via drinking water systems, such as those used at large animal production facilities, there are a lot of constraints that limit the suitability of many drugs, and especially benzimidazole carbamates, for this particular purpose.